Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation.

Abstract

Although dramatic clinical success has been achieved in acute promyelocytic leukemia (APL), the success of differentiating agents has not been reproduced in non-APL leukemia. A key barrier to the clinical success of arsenic is that it is not potent enough to achieve a clinical benefit at physiologically tolerable concentrations by targeting the leukemia cell differentiation pathway alone. We explored a novel combination approach to enhance the eradication of leukemia stem cells (LSCs) by arsenic in non-APL leukemia. In the present study, phosphatidylinositol 3-kinase /AKT/mammalian target of rapamycin (mTOR) phosphorylation was strengthened after As(2)S(2) exposure in leukemia cell lines and stem/progenitor cells, but not in cord blood mononuclear cells (CBMCs). propidium iodide-103, the dual PI3K/mTOR inhibitor, effectively inhibited the transient activation of the PI3K/AKT/mTOR pathway by As(2)S(2). The synergistic killing and differentiation induction effects on non-APL leukemia cells were examined both in vitro and in vivo. Eradication of non-APL LSCs was determined using the nonobese diabetic/severe combined immunodeficiency mouse model. We found that a combined As(2)S(2)/PI-103 treatment synergized strongly to kill non-APL leukemia cells and promote their differentiation in vitro. Furthermore, the combined As(2)S(2)/PI-103 treatment effectively reduced leukemia cell repopulation and eradicated non-APL LSCs partially via induction of differentiation while sparing normal hematopoietic stem cells. Taken together, these findings suggest that induction of the PI3K/AKT/mTOR pathway could provide a protective response to offset the antitumor efficacy of As(2)S(2). Targeting the PI3K/AKT/mTOR pathway in combination with As(2)S(2) could be exploited as a novel strategy to enhance the differentiation and killing of non-APL LSCs.

• Authors: Zhenya Hong, Min Xiao, Yang Yang, Zhiqiang Han, Yang Cao, Chunrui Li, Ying Wu, Quan Gong, Xiaoxi Zhou, Danmei Xu, Li Meng, Ding Ma, Jianfeng Zhou
• Journal: Carcinogenesis (Carcinogenesis) Vol. 32 Issue 10 Pg. 1550-8 (Oct 2011) ISSN: 1460-2180 [Electronic] England
• PMID: 21803735 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arsenicals
• Furans
• PI103
• Phosphoinositide-3 Kinase Inhibitors
• Pyridines
• Pyrimidines
• Sulfides
• arsenic disulfide
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Arsenicals (pharmacology)
• Blotting, Western
• Cell Differentiation (drug effects)
• Cell Line, Tumor (transplantation)
• Drug Synergism
• Furans (pharmacology)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism, pathology)
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplastic Stem Cells (drug effects)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Sulfides (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)